Friday, September 12, 2014

ADHD: Medication plus parent training may help kids with aggression

Combining two medications with parent training appears to improve anger, irritability and violent tendencies in children whose attention-deficit/hyperactivity disorder (ADHD) is coupled with severe aggression, a new study suggests.

"Augmented" therapy that consists of stimulant and antipsychotic drugs, along with parent training in behavioural management techniques, was rated more effective by parents than "basic" therapy pairing only the stimulant and parent training, researchers found.

"An important finding of this study was that at the end of nine weeks, approximately half of all children receiving basic therapy were still rated by their parents as being impaired... with symptoms interfering with school or social functioning," said study author Kenneth Gadow, a professor of psychiatry at Stony Brook University in New York.

"In the augmented group receiving three interventions for aggression, about one-quarter still, at the end of nine weeks, were rated by their parents as being impaired, and that suggests, even with highly effective therapies, that many of these children still have unmet treatment needs" " he added.

The drugs used in the study, published in the September issue of the Journal of the American Academy of Child and Adolescent Psychiatry, included the widely prescribed ADHD stimulant Concerta (methylphenidate) and the antipsychotic Risperdal (risperidone).

Approximately 11 percent of American children aged 4 to 17 have been diagnosed with ADHD, which includes symptoms such as impulsivity, hyperactivity, and difficulty focusing and controlling behavior, according to the U.S. Centers for Disease Control and Prevention.

As many as half of children with ADHD also display significant, disruptive aggression, according to an editorial accompanying the new research.

"This is very common among kids with ADHD, but unfortunately it complicates the picture for treatment," said Erin Schoenfelder, a clinical psychologist at Seattle Children's Hospital and assistant professor of psychiatry and behavioural health at University of Washington.

"It really is staggeringly high."

In the new research, Gadow and his colleagues divided a group of nearly 170 children aged 6 to 12 with ADHD and aggression problems into two treatment groups, basic and augmented.

The basic group received Concerta and their parents underwent behavioral management training.

The augmented group received Concerta and parental training as well, but also took the antipsychotic Risperdal. Both groups were followed for nine weeks.

While both groups of children displayed marked reduction in symptoms, improvement ratings varied depending on whether parents or teachers were making the assessment.

Parents reported that children on augmented therapy were less likely to be impaired socially or academically by their anger and irritability than children on basic therapy.

On the other hand, teachers found few differences in these measures.

Instead, teachers of those on augmented therapy reported significant drops in ADHD symptoms, especially impulsiveness, compared with teachers of children on basic therapy.

Gadow and Schoenfelder agreed that the conflicting parent-teacher ratings demonstrate a familiar concept: that children's behaviours vary in different settings, whether or not they have ADHD.

"Just like adults, they adapt their behaviours to be more appropriate for the setting they're in," Gadow said.

"People do differ, however, in their ability to modify their behaviour from one setting to the next, and some children are much more variable [in this regard]."

Schoenfelder said long-term evidence is needed indicating that combining Concerta and Risperdal is safe in children, but "it appears from this study that the combination was well-tolerated and something practitioners could [adjust the dosage of] effectively."

"Folks trying this type of treatment should have close monitoring," she added. "This is a starting point. It's a combination doctors may try when they see this blend of aggressive and hyperactive behaviours. It certainly will require adjustment . . . but it's exciting to find something helpful for a significant proportion of the kids studied."

The study authors pointed out that their findings only apply to children with ADHD who exhibit severe irritability and peer aggression.

They noted that the study's findings are not an indication of the ADHD population as a whole.

More Information: "Risperidone Added to Parent Training and Stimulant Medication: Effects on Attention-Deficit/Hyperactivity Disorder, Oppositional Defiant Disorder, Conduct Disorder, and Peer Aggression" http://www.jaacap.com/article/S0890-8567(14)00369-4/abstract

Thursday, August 21, 2014

Children with autism have extra synapses in brain

In a study of brains from children with autism, researchers found that autistic brains did not undergo normal pruning during childhood and adolescence. 

The images show representative neurons from autistic (left) and control (right) brains; the spines on the neurons indicate the location of synapses.

Credit: Guomei Tang, PhD and Mark S. Sonders, PhD/Columbia University Medical Center

Children and adolescents with autism have a surplus of synapses in the brain, and this excess is due to a slowdown in a normal brain "pruning" process during development, according to a study by neuroscientists at Columbia University Medical Center (CUMC).

Because synapses are the points where neurons connect and communicate with each other, the excessive synapses may have profound effects on how the brain functions.

The study was published in the August 21 online issue of the journal Neuron.

A drug that restores normal synaptic pruning can improve autistic-like behaviors in mice, the researchers found, even when the drug is given after the behaviours have appeared.

"This is an important finding that could lead to a novel and much-needed therapeutic strategy for autism," said Jeffrey Lieberman, MD, Lawrence C. Kolb Professor and Chair of Psychiatry at CUMC and director of New York State Psychiatric Institute, who was not involved in the study.

Although the drug, rapamycin, has side effects that may preclude its use in people with autism, "the fact that we can see changes in behaviour suggests that autism may still be treatable after a child is diagnosed, if we can find a better drug," said the study's senior investigator, David Sulzer, PhD, professor of neurobiology in the Departments of Psychiatry, Neurology, and Pharmacology at CUMC.

David Sulzer
During normal brain development, a burst of synapse formation occurs in infancy, particularly in the cortex, a region involved in autistic behaviours; pruning eliminates about half of these cortical synapses by late adolescence.

Synapses are known to be affected by many genes linked to autism, and some researchers have hypothesized that people with autism may have more synapses.

To test this hypothesis, co-author Guomei Tang, PhD, assistant professor of neurology at CUMC, examined brains from children with autism who had died from other causes.

Thirteen brains came from children ages two to 9, and thirteen brains came from children ages 13 to 20. Twenty-two brains from children without autism were also examined for comparison.

Dr. Tang measured synapse density in a small section of tissue in each brain by counting the number of tiny spines that branch from these cortical neurons; each spine connects with another neuron via a synapse.

By late childhood, she found, spine density had dropped by about half in the control brains, but by only 16 percent in the brains from autism patients.

"It's the first time that anyone has looked for, and seen, a lack of pruning during development of children with autism," Dr. Sulzer said, "although lower numbers of synapses in some brain areas have been detected in brains from older patients and in mice with autistic-like behaviours."


Clues to what caused the pruning defect were also found in the patients' brains; the autistic children's brain cells were filled with old and damaged parts and were very deficient in a degradation pathway known as "autophagy."

Cells use autophagy (a term from the Greek for self-eating) to degrade their own components. Using mouse models of autism, the researchers traced the pruning defect to a protein called mTOR.

When mTOR is overactive, they found, brain cells lose much of their "self-eating" ability and without this ability, the brains of the mice were pruned poorly and contained excess synapses.

"While people usually think of learning as requiring formation of new synapses, "Dr. Sulzer says, "the removal of inappropriate synapses may be just as important."

The researchers could restore normal autophagy and synaptic pruning, and reverse autistic-like behaviors in the mice, by administering rapamycin, a drug that inhibits mTOR.

The drug was effective even when administered to the mice after they developed the behaviors, suggesting that such an approach may be used to treat patients even after the disorder has been diagnosed.

Because large amounts of overactive mTOR were also found in almost all of the brains of the autism patients, the same processes may occur in children with autism.

"What's remarkable about the findings," said Dr. Sulzer, "is that hundreds of genes have been linked to autism, but almost all of our human subjects had overactive mTOR and decreased autophagy, and all appear to have a lack of normal synaptic pruning.

This says that many, perhaps the majority, of genes may converge onto this mTOR/autophagy pathway, the same way that many tributaries all lead into the Mississippi River.

Overactive mTOR and reduced autophagy, by blocking normal synaptic pruning that may underlie learning appropriate behaviour, may be a unifying feature of autism."

Alan Packer, PhD, senior scientist at the Simons Foundation, which funded the research, said the study is an important step forward in understanding what's happening in the brains of people with autism.

"The current view is that autism is heterogeneous, with potentially hundreds of genes that can contribute."

"That's a very wide spectrum, so the goal now is to understand how those hundreds of genes cluster together into a smaller number of pathways; that will give us better clues to potential treatments," he said.

"The mTOR pathway certainly looks like one of these pathways. It is possible that screening for mTOR and autophagic activity will provide a means to diagnose some features of autism, and normalizing these pathways might help to treat synaptic dysfunction and treat the disease."

Journal Reference: 
Guomei Tang, Kathryn Gudsnuk, Sheng-Han Kuo, Marisa L. Cotrina, Gorazd Rosoklija, Alexander Sosunov, Mark S. Sonders, Ellen Kanter, Candace Castagna, Ai Yamamoto, Zhenyu Yue, Ottavio Arancio, Bradley S. Peterson, Frances Champagne, Andrew J. Dwork, James Goldman, David Sulzer. "Loss of mTOR-Dependent Macroautophagy Causes Autistic-like Synaptic Pruning Deficits." Neuron, 2014; DOI: 10.1016/j.neuron.2014.07.040

ADHD children make poor decisions due to less differentiated learning processes

Attention-Deficit/Hyperactivity Disorder (ADHD) is one of the most common psychiatric disorders among school children. Pupils with ADHD often make poorer decisions than their unaffected classmates.

Researchers from the University of Zurich now discovered that different learning and decision-making mechanisms are responsible for these behaviors, and localized the underlying impairments in the brain.

Which shirt do we put on in the morning? Do we drive to work or take the train? From which takeaway joint do we want to buy lunch?

We make hundreds of different decisions every day. Even if these often only have a minimal impact, it is extremely important for our long-term personal development to make decisions that are as optimal as possible.

People with ADHD often find this difficult, however. They are known to make impulsive decisions, often choosing options which bring a prompt but smaller reward instead of making a choice that yields a greater reward later on down the line.

Researchers from the University Clinics for Child and Adolescent Psychiatry, University of Zurich, now reveal that different decision-making processes are responsible for such suboptimal choices and that these take place in the middle of the frontal lobe.

Mathematical models help to understand the decision-making processes
In the study, the decision-making processes in 40 young people with and without ADHD were examined.

Lying in a functional magnetic resonance imaging (fMRI) scanner to record the brain activity, the participants played a game where they had to learn which of two images carried more frequent rewards.

To understand the impaired mechanisms of participants with ADHD better, learning algorithms which originally stemmed from the field of artificial intelligence were used to evaluate the data.

These mathematical models help to understand the precise learning and decision-making mechanisms better.

"We were able to demonstrate that young people with ADHD do not inherently have difficulties in learning new information; instead, they evidently use less differentiated learning patterns, which is presumably why sub-optimal decisions are often made", says first author Tobias Hauser.

Multimodal imaging affords glimpses inside the brain
To study the brain processes that triggered these impairments, the authors used multimodal imaging methods, where the participants were examined using a combined measurement of functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) to record the electrical activity and the blood flow in the brain.

It became apparent that participants with ADHD exhibit an altered functioning in the medial prefrontal cortex, a region in the middle of the frontal lobe.

This part of the brain is heavily involved in decision-making processes, especially if you have to choose between several options, and in learning from errors.

Although a change in activity in this region was already discovered in other contexts for ADHD, the Zurich researchers were now also able to pinpoint the precise moment of this impairment, which already occurred less than half a second after a feedback, i.e. at a very early stage.

Psychologist Tobias Hauser, who is now researching at the Wellcome Trust Centre for Neuroimaging, University College London, is convinced that the results fundamentally improve our understanding of the mechanisms of impaired decision-making behaviour in people with ADHD.

The next step will be to study the brain messenger substances. "If our findings are confirmed, they will provide key clues as to how we might be able to design therapeutic interventions in future," explains Hauser.

More information: Tobias U. Hauser, Reto Iannaccone, Juliane Ball, Christoph Mathys, Daniel Brandeis, Susanne Walitza & Silvia Brem: Role of Medial Prefrontal "Cortex in Impaired Decision Making in Juvenile Attention-Deficit/Hyperactivity Disorder," in: JAMA Psychiatry, DOI: 10.1001/jamapsychiatry.2014.1093

Wednesday, August 20, 2014

Autism: ASU experts follow gut reaction in digestion treatment study

Clostridium difficile in the gut. The overgrowth of this dangerous bacteria can cause serious, life-threatening infections. 

About half of all children and adults with autism suffer from chronic gastrointestinal problems, causing frequent pain, discomfort and irritability.

Research out of Arizona State University suggests these gastrointestinal (GI) complications may be due, in part, to abnormal gut bacteria.

A new study approved by the U.S. Food and Drug Administration and led by Arizona State University will examine a novel treatment, called fecal microbiota transplant (FMT), for GI problems in children with autism.

The treatment involves transferring about 1,000 different species of live gut bacteria from a healthy donor that then act like a broad-spectrum probiotic treatment to restore normal gut bacteria.

FMT has been used to treat serious Clostrium difficle infections that kill up to 15,000 people each year in the United States.

Determining the safety and tolerability of using FMT to treat GI problems in children with autism is driving the study.

The FDA has approved a pilot treatment study of 20 children with autism, ages 7 to 17 years, and moderate to severe gastrointestinal problems.

Missing bacteria
Led by professor Rosa Krajmalnik-Brown, an expert on evaluating the composition of gut bacterial communities, and professor James Adams, director of the ASU Autism/Asperger's Research Program, the ASU research team published a scientific paper last year demonstrating that children with autism were missing several hundred species of gut bacteria compared to typical children.

"Our initial work found major differences in the gut bacteria of children with autism compared to typical children, and our subsequent work has confirmed those findings," said Krajmalnik-Brown.

"Children with autism seem to be missing hundreds of beneficial gut bacteria."

"Many children and adults with autism have chronic gut problems, sometimes lasting for many years and seriously affecting their quality of life," said Adams. "We think this treatment may be helpful."

The team's hypothesis is that FMT will "reseed" the gut with beneficial bacteria that will help diminish GI problems and possibly reduce autistic symptoms.

Several studies show that FMT may also be helpful in treating other GI problems, such as ulcerative colitis, Crohn's disease, inflammatory bowel disease, irritable bowel syndrome and chronic constipation.

Beneficial versus harmful
The human gut typically contains more than 1,000 different species of bacteria – most of them beneficial.

These bacteria help with digesting food, making certain vitamins, improving GI function and protecting against pathogenic bacteria.

However, there are a few dangerous bacteria, such as Clostidium difficile (C. difficile), which can cause serious, life-threatening infections.

C. difficile kills about 15,000 people per year in the U.S., but a single dose of FMT has been shown to cure C. difficile with 92 percent effectiveness, usually within a few days.

Collaborating with Northern Arizona University and University of Arizona, the ASU team will lead the treatment portion of the study, with the help of Sharon McDonough-Means, a developmental pediatrician involved in the care of children with autism and previous research studies.

Greg Caporaso at NAU, an expert in computational and statistical methods for studying communities of microorganisms, will analyze the effect of FMT on gut bacterial communities, and Matthew Sullivan at UA will investigate the viruses that infect gut bacteria, and thereby affect bacterial populations in the gut.

The new initiative is a follow-up to a previous study that demonstrated that treatment with a powerful oral antibiotic, vancomycin, led to a temporary improvement in both gut symptoms and symptoms of autism, presumably because it killed off harmful bacteria in the gut.

However, when the treatment was stopped, the benefits were lost, presumably because there was insufficient "reseeding" of the gut with beneficial bacteria.

Monday, August 18, 2014

The boundaries of reading apps for children

A series of binary discussions has been plaguing early reading instruction for quite some time now: phonics versus whole language, reading for pleasure versus reading for learning, digital versus paper books and it seems that there is a new tug-of-war on the educational horizon: spritzing versus slow reading.

Spritz is a recently developed programme that brings speed-reading to the untrained eye. Its makers claim that users can ultimately read 1,000 words per minute.

Their goal is to have 15% of the world's texts available in Spritz format by 2016.

But a message is coming from the other direction too. Those who revere and often romanticise printed books argue that we need to slow down.

They warn that the digital age has made us shallow readers who flit from text to text without taking anything in.

We have a clear conflict here. On one hand, lots of people want to read faster, especially now that there is more to read out there than at any other time in human history.

On the other hand, we hear that children in the digital age do not read in depth and the often cited culprit is the device in their hand – the technology that distracts them from picking up a good book.

Is a middle ground possible?

Reading and writing always come hand-in-hand. If readers whizz through rather than engage with texts, this will ultimately be reflected in the type of texts made available to them.

Spritz certainly responds to the zeitgeist to read fast in order to cope in a text-saturated era. You can also see this tendency in the proliferation of listicles on news websites and contents pages that tell you how long it will take you to read an article.

Some say that the only way to cope with large email volumes, is to binge-read our inboxes. Spritz could be thus seen as another invention that panders to our growing tendency to read more but in less depth.

At the same time, readers, be they young or old,need to be given time to pause and think with the author of a text.

Slow reading is, for many, synonymous with deep reading and reading for learning and there are in fact technological developments happening to help readers improve their deep reading, almost the antidote to Spritz.

There are reading annotation systems with built-in interactive discussion to help readers, students in particular, to better understand what they are reading.

These slow them down in their reading by asking them questions or prompting them to pause and take notes.

Similarly for younger readers, there are read-to-learn apps that explain vocabulary and thus help with reading comprehension.

So which approach is better for the contemporary reader? We can now whizz through every page on the internet by installing Spritzlet on our web browser.

It may not be long until slow reading widgets will become available to help us highlight information in onscreen texts, underline unfamiliar words, unpick abstract metaphors and provide links to facts.

In thinking about how to teach children to read effectively in digital age, we need to stop thinking in terms of slow and fast.

There is a difference between reading an email or a chemistry textbook or a novel. We use different reading formats for different contents, and different contents & formats for different purposes.

These different purposes come with different personal investments and hence different reading techniques.

There is already a disturbing disconnect between the content and format of reading happening in schools and outside the classrooms. Let's not increase this gap with another fictitious dichotomy.

Tuesday, August 5, 2014

Children with Autism: Blood-oxytocin levels in normal range

Spacefilling model of oxytocin. Created using ACD/ChemSketch 8.0, ACD/3D Viewer and The GIMP. 

Credit: Wikipedia.

Autism does not appear to be solely caused by a deficiency of oxytocin, but the hormone's universal ability to boost social function may prove useful in treating a subset of children with the developmental disorder, according to new findings from the Stanford University School of Medicine and Lucile Packard Children's Hospital Stanford.

Low levels of oxytocin, a hormone involved in social functioning, have for years been suspected of causing autism. Prior research seeking a link has produced mixed results.

Now, in the largest-ever study to test the purported connection, the range of blood oxytocin levels has been shown to be the same in children with autism as that observed in two comparison groups: children with autistic siblings and children without autistic siblings.

In other words, similar numbers of children with low, medium and high oxytocin levels were found in all three groups.

A paper describing the new findings will be published online Aug. 4 in Proceedings of the National Academy of Sciences (PNAS).

Although autism was not directly linked to oxytocin deficiency, the Stanford team found that higher oxytocin levels were linked to better social functioning in all groups.

All children with autism have social deficits, but in the study these deficits were worst in those with the lowest blood oxytocin and mildest in those with the highest oxytocin.

In the comparison groups, children's social skills also fell across a range that correlated to their oxytocin levels.

"Oxytocin appears to be a universal regulator of social functioning in humans," said Karen Parker, PhD, assistant professor of psychiatry and behavioural sciences and the lead author of the study.

"That encompasses both typically developing children as well as those with the severe social deficits we see in children with autism."

Autism is a developmental disorder that affects 1 of every 68 children in the United States. It is characterised by social and communication deficits, repetitive behaviours and sensory problems.

The new study included 79 children with autism, 52 of their unaffected siblings and 62 unrelated children without autism. All of the children were between the ages of 3 and 12.

"It didn't matter if you were a typically developing child, a sibling or an individual with autism: Your social ability was related to a certain extent to your oxytocin levels, which is very different from what people have speculated," said Antonio Hardan, MD, professor of psychiatry and behavioural sciences and the study's senior author.

Hardan is a child and adolescent psychiatrist who treats children with autism at the hospital.

"The previous hypotheses saying that low oxytocin was linked to autism were maybe a little bit simplistic," he said.

"It's much more complex: Oxytocin is a vulnerability factor that has to be accounted for, but it's not the only thing leading to the development of autism."

The researchers caution, however, that blood oxytocin measurements may be different than oxytocin levels in the cerebrospinal fluid bathing the brain, which they did not measure.

In addition to examining blood oxytocin levels, the researchers examined the importance of small variations in the gene coding for the oxytocin receptor.

Certain receptor variants were correlated to higher scores on standard tests of social ability, the study found.

The team also discovered that blood levels of oxytocin are highly heritable: The levels are influenced by inheritance to about the same degree as adult height, which is often described as being strongly influenced by genetics.

"What our study hints at is that social function may be heritable in families," Parker said.

The study will help to guide future research to determine whether oxytocin is a useful autism treatment.

The study's findings suggest that some children with autism, such as the subset of kids with autism who have naturally low oxytocin levels, or those with oxytocin receptor gene variants associated with worse social functioning, might benefit most from oxytocin-like drugs.

"Autism is so heterogeneous," Parker said. "If we can identify biomarkers that help us identify the patients most likely to benefit from a specific therapy, we expect that will be very useful."

More information: "Plasma oxytocin concentrations and OXTR polymorphisms predict social impairments in children with and without autism spectrum disorder," by Karen J. Parker et al. PNAS, www.pnas.org/cgi/doi/10.1073/pnas.1402236111

Monday, August 4, 2014

FASD: Prenatal alcohol exposure alters development of brain function

fMRI scan of working memory activation in typically-developing children. 

Credit: The Saban Research Institute

In the first study of its kind, Prapti Gautam, PhD, and colleagues from The Saban Research Institute of Children's Hospital Los Angeles found that children with fetal alcohol spectrum disorders (FASD) showed weaker brain activation during specific cognitive tasks than their unaffected counterparts.

These novel findings suggest a possible neural mechanism for the persistent attention problems seen in individuals with FASD.

The results of this study will be published in Cerebral Cortex on August 4.

"Functional magnetic resonance imaging (fMRI) has been used to observe brain activity during mental tasks in children with FASD, but we are the first to utilize these techniques to look at brain activation over time," says Gautam.

"We wanted to see if the differences in brain activation between children with FASD and their healthy peers were static, or if they changed as children got older."

FASD encompasses the broad spectrum of symptoms that are linked to in utero alcohol exposure, including cognitive impairment, deficits in intelligence and attention and central nervous system abnormalities.

These symptoms can lead to attention problems and higher societal and economic burdens common in individuals with FASD.

During the period of childhood and adolescence, brain function, working memory and attention performance all rapidly improve, suggesting that this is a crucial time for developing brain networks.

To study how prenatal alcohol exposure may alter this development, researchers observed a group of unaffected children and a group of children with FASD over two years.

They used fMRI to observe brain activation through mental tasks such as visuo-spatial attention, how we visually perceive the spatial relationships among objects in our environment, and working memory.

"We found that there were significant differences in development brain activation over time between the two groups, even though they did not differ in task performance," notes Elizabeth Sowell, PhD, director of the Developmental Cognitive Neuroimaging Laboratory at The Saban Research Institute and senior author on the manuscript.

"While the healthy control group showed an increase in signal intensity over time, the children with FASD showed a decrease in brain activation during visuo-spatial attention, especially in the frontal, temporal and parietal brain regions."

These results demonstrate that prenatal alcohol exposure can change how brain signaling develops during childhood and adolescence, long after the damaging effects of alcohol exposure in utero.

The atypical development of brain activation observed in children with FASD could explain the persistent problems in cognitive and behavioral function seen in this population as they mature.

Wednesday, July 30, 2014

Dyscalculia: Students Burdened by blunders with numbers

Between 3 and 6% of schoolchildren suffer from an arithmetic-related learning disability.

Researchers at Ludwig-Maximilians-Universitaet (LMU) in Munich now show that these children are also more likely to exhibit deficits in reading and spelling than had been previously suspected.

Addition and subtraction, multiplication and division are the four basic operations in arithmetic, but for some children, learning these fundamental skills is particularly challenging.

Studies show that they have problems grasping the concepts of number, magnitude, and quantity, and that they do poorly when asked to estimate relative amounts.

In mathematics classes they consistently lag behind, although they have little difficulty in subjects. In other words, they suffer from a highly specific learning disorder, which psychologists call 'dyscalculia'.

In total, about 5% of second- to fourth-graders manifest the condition.

Depending on which arithmetical operation is tested, the prevalence of the disorder varies between 3 and 6%.

These figures emerge from a new study carried out by LMU researchers led by Professor Gerd Schulte-Körne, Director of the Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, which has just been published.

The data are based on tests carried out on 1633 third- and fourth-graders in schools in the Munich area.

An arithmetic-related deficit can have a drastic effect on overall scholastic achievement and on the psychological development of the children affected.

They are reluctant to go to school because they are afraid of being perceived as failures and embarrassing themselves in front of their classmates.

Wherever possible, they resort to the use of avoidance strategies and develop a negative self-image. In the end, their performance also suffers in subjects in which they are perfectly capable.

Their lack of mathematical skills usually precludes them from going on to the type of secondary school for which their level of intelligence would otherwise qualify them, and impedes their chances of higher education.

Indeed, so long as they continue to get bad marks in mathematics, their chances of even completing secondary school remain low.

A promising training model
Schulte-Körne complains that the problems of children who suffer from dyscalculia are often overlooked in everyday classroom routine.

Furthermore, unlike the situation in the case of dyslexic disorders, there is no provision in Bavarian schools for adapting the learning environment so as to alleviate the burden on these children, he adds.

"This is not an appropriate response to a disorder that has a biological basis," he says.

It would, for example, be perfectly possible to give such children more time to complete their classwork in mathematics, to give them extra help, and even to refrain altogether from assigning a formal mark to their performance in the subject.

The new study, however, also shows that developmental deficits in cognition can affect more than one learning domain.

The LMU researchers found the prevalence of so-called comorbidity to be far higher than has been previously recognized.

According to psychologist Dr. Kristina Moll, first author on the new report, about 57% of children who have an arithmetic-related learning disorder also suffer from a reading or spelling disability.

"These data were quite a surprise for us", Schulte-Körne confesses. "This finding forces us to think again about diagnostic procedures for specific learning disorders but, above all, about how we can more effectively treat these conditions," Moll adds.

"These children need intensive and specific training and support. Otherwise, they are in danger of failing to achieve the scholastic success that would be compatible with their general level of intelligence."

As Schulte-Körne points out, effective approaches to the mitigation of dyscalculia are already available. These, however, require intensive, long-term training programs for the children affected.

In addition, the new study reveals that gender also appears to play a role in determining susceptibility to specific learning disorders, says Schulte-Körne: "While deficits in spelling are more prevalent among boys, girls are more likely to display dyscalculia. Reading difficulties, on the other hand, appear to be equally prevalent in both sexes."

The reasons for these striking findings remain unclear. Schulte-Körne suspects that biological factors are responsible, given that the learning environments experienced by both sexes are very similar.

Monday, July 21, 2014

Common gene variants account for most genetic risk for autism

The bulk of risk, or liability, for autism spectrum disorders was traced to inherited variations in the genetic code shared by many people. 

These and other (unaccounted) factors dwarfed contributions from rare inherited, non-additive and spontaneous (de novo) genetic factors 

Credit: Population-Based Autism Genetics and Environment Study

Most of the genetic risk for autism comes from versions of genes that are common in the population rather than from rare variants or spontaneous glitches, researchers funded by the National Institutes of Health (NIH) have found.

Heritability also outweighed other risk factors in this largest study of its kind to date. About 52 percent of the risk for autism was traced to common and rare inherited variation, with spontaneous mutations contributing a modest 2.6 percent of the total risk.

"Genetic variation likely accounts for roughly 60 percent of the liability for autism, with common variants comprising the bulk of its genetic architecture," explained Joseph Buxbaum, Ph.D., of the Icahn School of Medicine at Mount Sinai (ISMMS), New York City.

"Although each exerts just a tiny effect individually, these common variations in the genetic code add up to substantial impact, taken together."

Buxbaum, and colleagues of the Population-Based Autism Genetics and Environment Study (PAGES) Consortium, report on their findings in a unique Swedish sample in the journal Nature Genetics, July 20, 2014.

"Thanks to the boost in statistical power that comes with ample sample size, autism geneticists can now detect common as well as rare genetic variation associated with risk," said Thomas R. Insel, M.D., director of the NIH's National Institute of Mental Health (NIMH).

"Knowing the nature of the genetic risk will reveal clues to the molecular roots of the disorder. Common variation may be more important than we thought."

Although autism is thought to be caused by an interplay of genetic and other factors, including environmental, consensus on their relative contributions and the outlines of its genetic architecture has remained elusive.

Recently, evidence has been mounting that genomes of people with autism are prone to harboring rare mutations, often spontaneous, that exert strong effects and can largely account for particular cases of disease.

More challenging is to gauge the collective impact on autism risk of numerous variations in the genetic code shared by most people, which are individually much subtler in effect.

Limitations of sample size and composition made it difficult to detect these effects and to estimate the relative influence of such common, rare inherited, and rare spontaneous variation.

Differences in methods and statistical models also resulted in sometimes wildly discrepant estimates of autism's heritability, ranging from 17 to 50 percent.

Meanwhile, recent genome-wide studies of schizophrenia have achieved large enough sample sizes to reveal involvement of well over 100 common gene variants in that disorder.

These promise improved understanding of the underlying biology, and even development of risk-scores, which could help predict who might benefit from early interventions to nip psychotic episodes in the bud.

With their new study, autism genetics is beginning to catch up, say the researchers. It was made possible by Sweden's universal health registry, which allowed investigators to compare a very large sample of about 3,000 people with autism with matched controls.

Researchers also brought to bear new statistical methods that allowed them to more reliably sort out the heritability of the disorder.

In addition, they were able to compare their results with a parallel study in 1.6 million Swedish families, which took into account data from twins and cousins, and factors like age of the father at birth and parents' psychiatric history.

A best-fit statistical model took form, based mostly on combined effects of multiple genes and non-shared environmental factors.

"This is a different kind of analysis than employed in previous studies," explained Thomas Lehner, Ph.D., chief of NIMH's Genomics Research Branch.

"Data from genome-wide association studies was used to identify a genetic model instead of focusing just on pinpointing genetic risk factors. The researchers were able to pick from all of the cases of illness within a population-based registry."

Now that the genetic architecture is better understood, the researchers are identifying specific genetic risk factors detected in the sample, such as deletions and duplications of genetic material and spontaneous mutations.

Even though such rare spontaneous mutations accounted for only a small fraction of autism risk, the potentially large effects of these glitches makes them important clues to understanding the molecular underpinnings of the disorder, say the researchers.

"Within a given family, the mutations could be a critical determinant that leads to the manifestation of ASD in a particular family member," said Buxbaum.

"The family may have common variation that puts it at risk, but if there is also a de novo [spontaneous} mutation on top of that, it could push an individual over the edge."

"So for many families, the interplay between common and spontaneous genetic factors could be the underlying genetic architecture of the disorder."

More information: Gaughler T, Klei L, Sanders SJ, Bodea CA, Goldberg AP, Lee AB, Mahajan M, Manaa D, Pawitan Y, Reichert J, Ripke S, Sandin S, Sklar P, Svantesson O, Reichenberg A, Hultman CH, Devlin B, Roeder K, Buxbaum JD. Most genetic risk for autism resides with common variation. Nature Genetics, July 20, 2014. dx.doi.org/10.1038/ng.3039

Tuesday, June 17, 2014

MRI technique may help prevent ADHD misdiagnosis

This shows subgroup averages of parametric maps of MRI brain iron indices: magnetic field correlation (MFC: top row) and relaxation rates R2 (second row), R2*(third row), and R2' (bottom row). 

Parametric maps, masked for regions of interests (green): caudate nucleus (CN), putamen (PUT), globus pallidus (GP) and thalamus (THL), are shown for controls (n = 27), medication-naïve ADHD patients (ADHD-non-medicated; n = 12) and ADHD patients with a history of psychostimulant treatment (ADHD-medicated; n = 10). 

The ADHD-non-medicated subgroup displayed significantly reduced striatal (CN, PUT) and thalamic MFC compared to both controls and the ADHD-medicated subgroup. 

No significant differences were detected between the latter two groups. 

Credit: Radiological Society of North America 

Brain iron levels offer a potential biomarker in the diagnosis of attention deficit hyperactivity disorder (ADHD) and may help physicians and parents make better informed treatment decisions, according to new research published online in the journal Radiology.

ADHD is a common disorder in children and adolescents that can continue into adulthood. Symptoms include hyperactivity and difficulty staying focused, paying attention and controlling behavior. The American Psychiatric Association reports that ADHD affects 3 to 7 percent of school-age children.

Psychostimulant medications such as Ritalin are among the drugs commonly used to reduce ADHD symptoms.

Psychostimulants affect levels of dopamine, a neurotransmitter in the brain associated with addiction.

"Much debate and concern has emerged regarding the continual rise of ADHD diagnosis in the U.S. given that two-thirds of those diagnosed receive psychostimulant medications," said Vitria Adisetiyo, Ph.D., postdoctoral research fellow at the Medical University of South Carolina in Charleston, S.C.

"We wanted to see if we could identify brain iron as a potential noninvasive biomarker for medication-naïve ADHD to prevent misdiagnosis."

For the study, the research team measured brain iron levels in 22 children and adolescents with ADHD, 12 of whom had never been on medication for their condition (medication naïve), and 27 healthy control children and adolescents using a magnetic resonance imaging (MRI) technique called magnetic field correlation imaging.


The technique was introduced in 2006 by study co-authors and faculty members Joseph A. Helpern, Ph.D., and Jens H. Jensen, Ph.D. No contrast agents were used, and blood iron levels in the body were measured using a blood draw.

The results showed that the 12 ADHD medication-naïve patients had significantly lower brain iron levels than the 10 ADHD patients who had been on psychostimulant medication and the 27 children and adolescents in the control group.

In contrast, ADHD patients with a history of psychostimulant medication treatment had brain iron levels comparable to controls, suggesting that brain iron may increase to normal levels with psychostimulant treatment.

"Our research suggests that iron absorption into the brain may be abnormal in ADHD given that atypical brain iron levels are found even when blood iron levels in the body are normal," Dr. Adisetiyo said.

"We found no differences in blood iron measures between controls, medication-naïve ADHD patients or pscyhostimulant-medicated ADHD patients."

If the results can be replicated in larger studies, magnetic field correlation might have a future role in determining which patients would benefit from psychostimulants—an important consideration because the drugs can become addictive if taken inappropriately and lead to abuse of other drugs like cocaine.

"We want the public to know that progress is being made in identifying potential noninvasive biological biomarkers of ADHD which may help to prevent misdiagnosis," Dr. Adisetiyo said.

"We are currently testing our findings in a larger cohort to confirm that measuring brain iron levels in ADHD is indeed a reliable and clinically feasible biomarker."

More information: "Multimodal MR Imaging of Brain Iron in Attention Deficit Hyperactivity Disorder: A Non-invasive Biomarker that Responds to Psychostimulant Treatment?" Radiology, 2014.